+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-35543 | ||||||||||||||||||||||||||||||||||||
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タイトル | Cryo-EM structure of PI3Kalpha in complex with compound 16 | ||||||||||||||||||||||||||||||||||||
マップデータ | |||||||||||||||||||||||||||||||||||||
試料 |
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キーワード | Phosphoinositide 3-kinase / drug target / ligand / binding pocket / chemical scaffold / STRUCTURAL PROTEIN | ||||||||||||||||||||||||||||||||||||
機能・相同性 | 機能・相同性情報 perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of endoplasmic reticulum unfolded protein response / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / regulation of cellular respiration / RHOF GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / negative regulation of stress fiber assembly / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / CDC42 GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / PI3K Cascade / RET signaling / intercalated disc / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / T cell differentiation / RHOG GTPase cycle / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / endothelial cell migration / positive regulation of TOR signaling / RHOA GTPase cycle 類似検索 - 分子機能 | ||||||||||||||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) | ||||||||||||||||||||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.05 Å | ||||||||||||||||||||||||||||||||||||
データ登録者 | Zhou Q / Liu X / Neri D / Li W / Favalli N / Bassi G / Yang S / Yang D / Vogt PK / Wang M-W | ||||||||||||||||||||||||||||||||||||
資金援助 | 中国, 米国, 11件
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引用 | ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Structural insights into the interaction of three Y-shaped ligands with PI3Kα. 著者: Qingtong Zhou / Xiao Liu / Dario Neri / Wenxin Li / Nicholas Favalli / Gabriele Bassi / Su Yang / Dehua Yang / Peter K Vogt / Ming-Wei Wang / 要旨: Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently ...Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα. | ||||||||||||||||||||||||||||||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_35543.map.gz | 59.7 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-35543-v30.xml emd-35543.xml | 19.7 KB 19.7 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_35543_fsc.xml | 9.1 KB | 表示 | FSCデータファイル |
画像 | emd_35543.png | 59 KB | ||
その他 | emd_35543_half_map_1.map.gz emd_35543_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-35543 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35543 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_35543_validation.pdf.gz | 763 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_35543_full_validation.pdf.gz | 762.6 KB | 表示 | |
XML形式データ | emd_35543_validation.xml.gz | 16.3 KB | 表示 | |
CIF形式データ | emd_35543_validation.cif.gz | 21.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35543 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35543 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_35543.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.071 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_35543_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_35543_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : Human PI3Kalpha in complex with compound 16
全体 | 名称: Human PI3Kalpha in complex with compound 16 |
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要素 |
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-超分子 #1: Human PI3Kalpha in complex with compound 16
超分子 | 名称: Human PI3Kalpha in complex with compound 16 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit ...
分子 | 名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO / EC番号: phosphatidylinositol 3-kinase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 127.822578 KDa |
組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
配列 | 文字列: MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR ...文字列: MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK IN HDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KES LYSQLP MDCFTMPSYS RRISTATPYM NGETSTKSLW VINSALRIKI LCATYVNVNI RDIDKIYVRT GIYHGGEPLC DNVN TQRVP CSNPRWNEWL NYDIYIPDLP RAARLCLSIC SVKGRKGAKE EHCPLAWGNI NLFDYTDTLV SGKMALNLWP VPHGL EDLL NPIGVTGSNP NKETPCLELE FDWFSSVVKF PDMSVIEEHA NWSVSREAGF SYSHAGLSNR LARDNELREN DKEQLK AIS TRDPLSEITE QEKDFLWSHR HYCVTIPEIL PKLLLSVKWN SRDEVAQMYC LVKDWPPIKP EQAMELLDCN YPDPMVR GF AVRCLEKYLT DDKLSQYLIQ LVQVLKYEQY LDNLLVRFLL KKALTNQRIG HFFFWHLKSE MHNKTVSQRF GLLLESYC R ACGMYLKHLN RQVEAMEKLI NLTDILKQEK KDETQKVQMK FLVEQMRRPD FMDALQGFLS PLNPAHQLGN LRLEECRIM SSAKRPLWLN WENPDIMSEL LFQNNEIIFK NGDDLRQDML TLQIIRIMEN IWQNQGLDLR MLPYGCLSIG DCVGLIEVVR NSHTIMQIQ CKGGLKGALQ FNSHTLHQWL KDKNKGEIYD AAIDLFTRSC AGYCVATFIL GIGDRHNSNI MVKDDGQLFH I DFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PE LQSFDDI AYIRKTLALD KTEQEALEYF MKQMNDAHHG GWTTKMDWIF HTIKQHALN UniProtKB: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform |
-分子 #2: Phosphatidylinositol 3-kinase regulatory subunit alpha
分子 | 名称: Phosphatidylinositol 3-kinase regulatory subunit alpha タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 83.623203 KDa |
組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
配列 | 文字列: MAEGYQYRAL YDYKKEREED IDLHLGDILT VNKGSLVALG FSDGQEARPE EIGWLNGYNE TTGERGDFPG TYVEYIGRKK ISPPTPKPR PPRPLPVAPG SSKTEADVEQ QALTLPDLAE QFAPPDIAPP LLIKLVEAIE KKGLECSTLY RTQSSSNLAE L RQLLDCDT ...文字列: MAEGYQYRAL YDYKKEREED IDLHLGDILT VNKGSLVALG FSDGQEARPE EIGWLNGYNE TTGERGDFPG TYVEYIGRKK ISPPTPKPR PPRPLPVAPG SSKTEADVEQ QALTLPDLAE QFAPPDIAPP LLIKLVEAIE KKGLECSTLY RTQSSSNLAE L RQLLDCDT PSVDLEMIDV HVLADAFKRY LLDLPNPVIP AAVYSEMISL APEVQSSEEY IQLLKKLIRS PSIPHQYWLT LQ YLLKHFF KLSQTSSKNL LNARVLSEIF SPMLFRFSAA SSDNTENLIK VIEILISTEW NERQPAPALP PKPPKPTTVA NNG MNNNMS LQDAEWYWGD ISREEVNEKL RDTADGTFLV RDASTKMHGD YTLTLRKGGN NKLIKIFHRD GKYGFSDPLT FSSV VELIN HYRNESLAQY NPKLDVKLLY PVSKYQQDQV VKEDNIEAVG KKLHEYNTQF QEKSREYDRL YEEYTRTSQE IQMKR TAIE AFNETIKIFE EQCQTQERYS KEYIEKFKRE GNEKEIQRIM HNYDKLKSRI SEIIDSRRRL EEDLKKQAAE YREIDK RMN SIKPDLIQLR KTRDQYLMWL TQKGVRQKKL NEWLGNENTE DQYSLVEDDE DLPHHDEKTW NVGSSNRNKA ENLLRGK RD GTFLVRESSK QGCYACSVVV DGEVKHCVIN KTATGYGFAE PYNLYSSLKE LVLHYQHTSL VQHNDSLNVT LAYPVYAQ Q RR UniProtKB: Phosphatidylinositol 3-kinase regulatory subunit alpha |
-分子 #3: N-[(2S)-1-(ethylamino)-1-oxidanylidene-3-[4-(2-quinoxalin-6-yleth...
分子 | 名称: N-[(2S)-1-(ethylamino)-1-oxidanylidene-3-[4-(2-quinoxalin-6-ylethynyl)phenyl]propan-2-yl]-2,3-dimethyl-quinoxaline-6-carboxamide タイプ: ligand / ID: 3 / コピー数: 1 / 式: 7TZ |
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分子量 | 理論値: 528.604 Da |
Chemical component information | ChemComp-7TZ: |
-分子 #4: water
分子 | 名称: water / タイプ: ligand / ID: 4 / コピー数: 7 / 式: HOH |
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分子量 | 理論値: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 1.0 mg/mL |
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緩衝液 | pH: 7.6 |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 70.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: OTHER |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 1.5 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |